USP24 and NF-κB formed a positive regulatory loop increases BMP4 to induce cardiac fibrosis during lung cancer progression

Abstract Cardiovascular diseases (CVD) and cancer are the leading causes of death worldwide each year. This study showed that EGFR L858R -induced lung cancer mice exhibited reduced heart function, which could be improved by knocking out USP24 or treating with a specific USP24 inhibitor, USP24-i-101. Bone morphogenetic protein 4 (BMP4), a member of the TGF-β superfamily, in cancer cells and M2 macrophages, is inhibited by USP24-i-101 or by silencing USP24. NF-κB can be recruited to the promoter of BMP4 to enhance its transcription activity. There is a positive feedback regulation between USP24 and NF-κB, increasing transcriptional activity to induce BMP4 expression in cancer cells and M2 macrophages. Secreted BMP4 from macrophages and cancer cells activates the SMAD pathway in cardiomyocytes, inducing fibrosis-related gene expression. In cardiac myoblasts, H9c2 cells, USP24 is also positively feedback regulated with BRD7 to activate the Wnt/β-catenin pathway, thereby inducing fibrosis-related gene expression. In summary, the positive feedback regulation between USP24 and NF-κB in lung cancer cells and M2 macrophages enhances BMP4 expression, causing fibrosis of cardiac myoblasts. Additionally, the positive feedback regulation between USP24 and BRD7 in cardiac myocytes activates the Wnt/β-catenin pathway, leading to fibrosis of myoblasts. Targeting USP24 with USP24-i-101 in lung cancer patients may improve cardiac activity by inhibiting heart tissue fibrosis.